Herpesvirus saimiri (HVS) is a member of the gamma subfamily of herpesviruses. Analysis of HVS genomic sequences has revealed that HVS is most closely related to Kaposi's sarcoma-associated herpesvirus (KSHV) and to rhesus monkey rhadinovirus (RRV). HVS naturally infects squirrel monkeys without causing disease. Infection of marmosets and other New World primates with HVS, however, results in rapidly progressing malignant T cell lymphomas. Our research has been directed toward understanding the molecular mechanisms of oncogenic transformation by HVS. We have developed streamlined procedures for the isolation of deletion mutant, point mutant and recombinant HVS. These procedures have allowed us to study the role of STP (saimiri transforming protein), tip (tyrosine kinase interacting protein), orf14 (superantigen homolog), vIL-17, vbcl-2 and vCD59 in replication and transformation. HVS contains additional open reading frames which could possibly contribute to transformation by this virus: v-cyclin; vGCR (G protein coupled receptor); vFLIP (FLICE inhibitory protein). Our continuing studies will be focused on the importance and role of these three viral gene products in oncogenic transformation by HVS. Mutant strains of HVS will be constructed with v-cyclin, vGCR or vFLIP gene deleted individually. We will examine the effects of these deletions on T lymphocyte immortalization in vitro, lymphoma induction in vivo and persistent infection. Detailed functional studies on the biochemical activities of STP and tip will be performed in order to understand their roles in HIV-induced oncogenic transformation. The information obtained from these studies will provide insights into the strategies used by primate rhadinoviruses for replication and persistence and into the mechanisms of pathogenesis.